The adult brain is constantly changing. New neurons are added daily in the dentate gyrus (DG) of the adult mammalian brain and are thought to be involved in hippocampal plasticity. However, the function of hippocampal neurogenesis remains elusive because newborn neurons are sparsely distributed, making it difficult to manipulate more than a few cells in intact circuit with electrodes. We propose to use novel photostimulation and optical imaging technologies to manipulate newborn neuron populations directly and selectively in intact hippocampal circuits and in vivo, with high spatial and temporal resolution. Recent studies indicate that these adult-born hippocampal neurons exhibit greater excitability and a high propensity for potentiation during early stages of their maturation. Several behavioral studies have also correlated learning performance with the survival of immature newborn neurons, suggesting that neurogenesis has a significant role in hippocampal-dependent memory formation. Yet whether newborn neurons directly participate in hippocampal plasticity remains to be determined. This study will provide the first circuit-level mechanistic study of neurogenesis in hippocampal processing and memory formation. We hypothesize that newborn neurons recruit specific classes of interneurons to modulate local network activity in the hippocampus and are crucial elements for associative memory formation. Novel light-gated ion channels and activity sensors will be used to facilitate noninvasive and millisecond-control of newborn neuron activation. In Specific Aims 1 and 2 we will characterize the circuit integration of hippocampal newborn neurons by selective stimulation or inhibition. The post-stimulation circuit dynamics will be monitored using calcium imaging. In Specific Aim 3 we will determine the contribution of newborn neurons to formation and recall of associative memory by cell-specific in vivo activation or inhibition during eyeblink trace conditioning trials. Understanding the functional of newborn neurons is highly relevant to translational regenerative medicine. The results from this study will help guide neural stem cell transplantation studies. Also, the technologies developed in this study will be a widely useful tool for medical research in functional neural regeneration. [unreadable] [unreadable]